Infertility and other reproductive disorders are among the many health-related consequences of obesity. Circulating concentrations of leptin, a hormone secreted by fat cells, become greatly elevated in obesity and can lead to the development of leptin resistance. In addition to its role in regulating metabolism and appetite, leptin participates in control of reproduction. Gonadotropic control of the ovaries is dependent upon leptin modulation in the hypothalamus, and evidence suggests that leptin plays a significant role in the direct regulation of ovarian function. Hyperleptinemia has been correlated with impaired reproductive function. Nevertheless, leptin appears to exert generally positive effects on ovarian function under experimental conditions. A possible explanation for this paradox, which has not been investigated, is that the association between high leptin levels and diminished reproductive function is due to leptin resistance. The proposed research will test the novel hypothesis that a state of leptin resistance in ovarian target cells contributes to diminished fertility in obesity. Two specific aims will be addressed, (1) to determine whether adult onset obesity in mice leads to ovarian leptin resistance and (2) to determine the relationship between ovarian leptin resistance and follicular dynamics and oocyte developmental competence. Mice possessing a specific deletion in the promoter region of the agouti protein gene, i.e. lethal yellow mice (C57BL/6J-Ay/a), develop adult-onset obesity, progressive loss of fertility, elevated circulating leptin levels, and hypothalamic leptin resistance. Specific markers of ovarian leptin resistance and measurements of ovarian function will be compared between Ay/a mice and same strain non-mutant black (C57BL/6J a/a) mice at three distinct ages, 100, 150, and 200 days. To dissociate central from ovarian effects, endogenous gonadotropin secretion will be suppressed by treatment with GnRH antagonist. Ovaries will be stimulated with equine chorionic gonadotropin (eCG) and ovulation induced with human chorionic gonadotropin (hCG). The overall objective of the proposed research is to answer the novel question of whether leptin resistance is manifested in the ovary, and if it is related to impaired ovarian function. The results will hopefully provide a strong foundation for future studies to elucidate the precise role of leptin and leptin resistance in ovarian function and fertility.